N-substituted methoxyphenoxy-ethylamines



United States Patent 3,192,253 N-SUBSTITUTED METHGXYPHENGXY- 1 ETHYLAMIVES Ronald J. Boscott, Deal, Kent, Joachim Augstein, Temple Ewell, near Dover, Kent, William C. Austin, Hatfield 5 Heath, Bishops Stortt'ord, and Charles A. Bartram,

Deal, Kent, England, assignors to Chas Pfizer 8; Co.,

Inc, New York N.Y., a corporation of Delaware No Drawing. Filed Apr. 7, 1961, Ser. Bio-101,326 Claims priority, application Great Britain, Apr. 22, 1959,

13,683/59; Jan; 29, 1960, 3,238/60; Apr. 7, 1960,

12,333/60; July 14, 1960, 24,506/60 14 Claims. (Cl. 260-501) This application is a continuation-in-part of our copending application Serial No. 23,133, filed April 19, 1960, and now abandoned. This invention is concerned with new and useful therapeutic agents. More particularly, it is concerned with substituted alkylamines and their acid addition salts which are valuable in the treatment of hypertension.

Compounds of the present invention can be represented by the formula:

,carbonamide phenyl, alkyl carbonamide, dialkyl carbonamide, each alkyl group attached to the carbonamide nitrogen atom having from 1 to 3 carbon atoms, hydroxybenzyl, alkylbenzyl wherein the alkyl radical has from 1 to 4 carbon atoms, methoxybenzyl, ethoxybenzyl,

, chlorobenzyl and bromobenzyl; Z is selected from the group consisting of H2) x- Hz- 2) y, 2) F 1 H 2) y, H2) X I H 2) y x and y are each an integer from 1 to 3 and x plus y equals an integer from 2 to 5; p and q are each Whole numbers from 0 to 2 and p plus q equals an integer from 2 to 4; and z equals an integer from 1 to 4; For simpli fication, the first four members of Z may also be defined as (CH2)1. CH(CHg) 1%. wherein R is hydrogen, hydroxy, methoxy or C(CH2).

Included also within the scope of this invention are the pharmaceutically acceptable acid addition salts of these novel products, that is, acid salts suchas the hydrochloride, sulfate, acetate, phosphate, ascorbate, citrate, maleate, trartrate, di-(p-toluoyl)tartrate, embonate, amsonate and parnoate.

The compounds of this invention have utility as physiologically active agents and particularly as hypotensive est concentration of the active ingredient.

p CC

agents which .act upon the central nervous system and decrease abnormally high blood pressures to more normal values. In addition to this property certain of these valuable and novel compounds also exhibit sedative activity, adrenaline potentiation and adrenolytic activity.

Within the above generic class of compounds, certain subgroups are preferred. One of these subgroups are those wherein R is (CH H, z being a number of 0 to 1, R is hydrogen or hydroxy, R is alkenyl as defined above and R is methoxy. The compounds wherein R is alkanoyloxy are active via oral administration only and are, in some instances, desirable because of their solubility characteristics relative to those of the corresponding nonacylated compounds. Other desirable subclasses are as follows:

(b) Wherein R is methoxy, R is (CH I-I wherein z is a number from 0 to 1, R is CN and R is hydroxy or hydrogen.

Particularly desirable compounds are those in each of the above identified subclasses wherein the ,R methoxy is ortho to the OCH CH radical.

The compounds of this invention may be administered alone but are generally administered as a composition with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practicev For example, they may be administered orally in the form of tablets containing such excipicuts as starch, milk sugar, certain types of clay, etc. They may be administered in capsules either alone or in admixture with the same or equivalent excipients. They may also be administered orally in the form of elixirs or oral suspensions which may contain flavoring or coloring agents. They may be injected parenterally, that is, for example, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough saline or glucose to make the solution isotonic.

Dosage units containing from 0.1 mg. to 100 mg. are useful. Those dosage unit forms which are prepared for subcutaneous administration will usually contain the low- Dosage forms for intramuscular administration will be somewhat higher and those dosage forms intended for oral administration, for example, elixirs, tablets or capsules will contain still more of the active ingredient.

As noted above the compositions of this invention may take a variety of forms. Various diluents may be employed and the percentage of active ingredients may be varied. It is necessary that the active ingredient constitute a proportion of the composition such that a suitable dosage form will be obtained. Obviously several dosage unit forms may be administered at about the same time.

Althoughcompositions with less than 0.05 by weight of active ingredients are suitable, it is preferred to use compositions containing at least 0.05% of the active agent. Activity increases with the concentration of the active agent. The percentage by weight of active agent may be 10, 50, 75, or even higher. Dosage unit forms may be prepared with a minor proportion of a carrier and a major proportion of active materials.

Daily doses of the order of 0.1 mg. to 5 mg./kg. of body weight per day are effective in lowering blood pressure in lower animals. Therefore, the concentration of the active ingredient in the carrier will be least about 0.1% by weight.

As might be expected, certain of these compounds are more'active than others. For example, in a given compound better hypotensive activity is shown when R represents a substituent group in the ortho-position. In this respect the methoxy group imparts a greater degree of activity than do the other groups defined by R In each case, however, the ortho position is preferred.

The valuable and novel compounds of this invention may be prepared by any of several methods. One of these methods consists in reacting the appropriate phenoxyethyl halidewith the proper amine derivative of the formula: R NH-ZOR wherein R R and Z are defined above in the presence of an acid acceptor. In order to realize maximum yields of the desired substituted alkylamines, sufficient acidacceptor should be used to neutralize completely the hydrogen halide released as a result of the reaction. The acid acceptor may be an alkali metal hydroxide, an excess of the amine reactant, or a tertiary amine, such as, pyridine or dimethylaniline. The mole ratio of amine derivative to phenoxyethyl halide may, of course, be less than, equal to: or greater "than one. However, the mole ratio of amino derivative to halide derivative should be at least one and suflicient acid acceptor must be present to react completely with the hydrogen halide released as a result of the condensation reaction to assure the best yield.

A second method of preparation consists in reacting a suitable phenoxyethyl amine with the appropriate chloride of one formula: Cl-ZOR or the corresponding bromides wherein Z and R are as previously defined, under conditions so as to obtain a maximum yield of the desired product as mentioned above.

Although these compounds. can be prepared by methods other than those outlined above and also by modifications which will apear to, those skilled in the art, we prefer to use the procedures described in the specific examples since they are easily. carried out, require no complicated apparatus and involve a minimum of manipulative steps. I

The. compounds of this invention are, for the most part, pale yellow viscid liquids which are diflicultly solubleinwater but soluble inorganic solvents, such as alcohols, acetone, ethyleneglycol, and ether. Those that exist as solids are generally waxy solids of low melting point.-

The inorganic or organic acid addition salts of the compounds of this invention can be prepared by neutralization of the substituted alkylamines with the desired acid. The acid addition salts serve as a useful means for isolating the products of this invention from solutions, particularly from organic solutions, in a form from which the free base easily be regenerated. In addition, certain of the pharamaceutically acceptable acid addition salts, such as the hydrochloride, sulfate, acetate, phosphate, citrate, are soluble in water and hence. useful for the preparation of pharmaceutical solutions for the treatment of hypertension. Other pharmaceutically acceptable salts, for example, the pamoate, embonate and amsonate are water insolube and, therefore, valuable for the preparation of pharmaceutical suspensions useful in hypertension therapy.

The hydrochloride salts are conveniently prepared'by passage of dry hydrogen chloride into a solution of the substituted alkylamine inan organic solvent. Neutralization of the substituted alkylamines in aqueous solution followed by concentration and/or precipitation with a water miscible organic solvent produces'the hydrochloride salts, generally as white crystalline solids. When an unsaturated aliphatic group is present in the molecule, the hydrochloride salts are prepared by treatment with alcholic hydrogen chloride containing the theoretical amount of hydrogen chloride. The salts are recovered by removal of the solvent at low temperature;. preferably, under reduced pressure.

In order to illustrate this invention more fully, but without thereby limiting it, the following examples are given.

GENERAL PROCEDURE Typical methods for preparing the products of this invention are summarizedbelow.

Method A.The amine reactant,

is stirred and heated to to C. The appropriate phenoxyethyl halide,-generally the chloride, is added in a 1 to 6 molar ratio over aperiod of one hour after which the mixture is'heated an additional four hours at C. to C. The mixture is then cooled and a 40% solution containing 1 mole of sodium hydroxide, equivalent to the halide used, is added. The mixture is stirred for five minutes then extractedwith methylene chloride or ether, the extract dried and solvent removed. The residueis distilled in vacuo.

Method B.-This method is similar to Method A but uses the appropriate phenoxyethylamine andthe chlorocompound of the formula CLZVOR as reactants in a 2 to 1 molar ratio.

Method C.The amine reactant, RQNH.-Z-OR and the appropriate phenoxyethyl chloride are reacted in a 1 to 1 molar ratio in alcohol solution C50-100 m1. on a 0.1 molar scale) ,with sodium bicarbonate (1 mole). as neutralizing agent. After 24 hours, the mixture is cooled, filtered and the alcohol removed. The residue is purified by distillation in vacuo.

Method D.The procedure of Method C is'followed but using the appropriate phenoxyethyla'mine and the chloro compound CL-ZO-R as reactants.

Method E.The procedure of Method B is followed but using the bromo compound in placeof the chloroanalog, a half-hour addition at 80 0., followed by heating at 80 to 100 C. for one-half hour.

The following examples further illustrate the various methods of preparation. They also illustrate typical compounds coming within the scope of the present invention.

Example I I The following compounds are prepared by the methods described above using a 2 to 1 molar ratio of amine:

TABLE I Pressure, Method mm. Hg

mmnmmmnnnnmnm wwoewwww t See footnotes at end of table.

TABLE I.-Continued TABLE II.C0ntinued Example II phenoxy)ethylamine (10 g.) and acetic anhydride (15 g.) are mixed and refluxed for ten minutes. The resultant mixture is poured into iced water, made alkaline with ammonia, and the resultant mixture extracted with ether. The ether extract is shaken with dilute hydrochloric acid to remove unchanged base then dried and the ether dis-.

tilled oil. The residue is then passed down a column of alumina and eluted with 2% aqueous acetic acid. The first fraction is collected, made alkaline and extracted with ether. Removal of the ether gives an almost colorless oil.

Analysis.-Calcd. for C H NO C, 62.47% H, 7.40%; N, 3.84%. Found: C, 62.29%; H, 7.55%; N, 3.95%.

In like manner, the products of Example I are converted to their acetylated derivatives.

Example V.N- [3- (2'-pr0pyn-1-oxy propyl-N-Z- (2 methoxyph enoxy -cthyl] -N-methy [amine 2,3-dibromo-propene-1 (5 g., prepared according to Gustavson and Demjarov, J. prakt. Chem. 38, 201, 1888) is added dropwise over a period of one hour to N-[2-(2- methoxyphenoxy) ethyl] -N-rnethyl-3 -am-inoprop anol (24.2 g.). Upon completion of addition, the mixture is heated to 150 C. for one hour after which it is cooled and treated with a solution of sodium hydroxide (1 g.) in

20 m1. of water. The product is extracted with ether and recovered by evaporation of the dried ethereal extract.

Dehydrohalogenationof the monohalogenated ether thus produced is accomplished by reaction with sodamide in liquid ammonia according to the procedure of Parcell and Pollard, J. Am. Chem. Soc. 72, 2385 (1950). The sodium acetylide. derivative produced is decomposed with water to give the desired acetylenic ether which upon distillation in high vacuum is obtained as a viscous yellow oil.

Example VI. N (2 acetoxy 3 allyloxypropyl) N- [2-(2'-methoxyphen0xy)cthyl1amine N (2 hydroxy 3 allyloxypropyl) N [2 (2- me-th-oxyphenoxy)ethyl]-amine hydrochloride (2 g., 1 mol.) and acetic anhydride (0.64 g., 1 mol.) are heated on a steam bath for. one hour. The mixture is then cooled and poured into iced Water. "The resultant acid solution .is extracted with. ether. to remove the diacetyll and N- acetyl'compounds and then made alkaline with powdered Example VII.N (3 allyloxy 2 butyrylxypr0pyl)- N -2- (2'-methoxy phenoxy ethy l-butyramide N (3 allyloxy 2 hydroxypropyl) N [2 (2- rnethoxyphenoxy)ethyl]iamine- (7.0 g.) and butyr-ic anhydride (12 g.) are boiled under reflux for one hour. The mixture is then cooled and poured into 0.880 N ammonia in the cold,keeping the temperature between 0 C.-5 C. It is then extracted with ether, the ether solution dried, and the ether then removed.

After several distillations in vacuo, an almost colorless oil, boiling point 182 C.-184 obtained.

* Analysis.-Calcd. for C23H35NO5 C, H, Found: C, 65.66%; H, 8.47%; N, 3.26%.

In like manner, but,using the proper acylating agent, the products of Examples I and II wherein R is hydroxy are converted to their diacylated derivatives wherein the acyl groups are the propionyl, acetyl, formyl and butyryl.

Example VIII.-N (3(2' mcthoxyphenoay) propyl) N-' [2- (2-methoxyphen0xy)ethyl1acetamide N (3 (2 methoxyphenoxy)propyl) N [2 (2'-. methoxyphenoxy)ethyllarnine is dissolved in pyridine (50 ml.) and acetyl chloride (3 g.) slowly added to the mixture. After a half hour, Water is added and the. aqueous layer then extracted with ether. The ether layer is extract-ed with dilute hydrochloric acid, washed, dried and the ether removed, leaving behind a yellow oil: The oil crystallizes on addition of petroleum ether and is further recrystallized from petroleum ether (60 C. 80 C.). Melting point: 65.5 C.67.5 C. T

Analysis.-Calcd. for C H NO C, 67.54%; H, 7.29%; N, 3.75%. Found: C, 67.45%; H, 7.02%; N, 3,63%.

ExamplepIX Example X.N (3 amyloxy 2 hydroxypropyl) N- [2- (2'-hydroxyphenoxy ethyl] amine hydrochloride N (3 amyloxy 2 hydroxypr-opyl) N [2 (2'- benzyloxyphenoxy)ethylJa-mine (l g.) in 95% ethanol (15 ml.) with palladiumcharcoal (0.2 g.) as catalyst is hydrogenated at room temperature and pressure. The

theoretical quantity of hydrogen is absorbed in 20 minutes. The catalyst is filtered ofl? and the solvent distilled off, leaving a violet oil. The oil is dissolved in ether and hydrogen chloride passed in gently with cooling. The white crystalline hydrochloride which forms is collected and recrystallized from ethyl acetate/ethanol (10:1). Melting point: 182.5 C.l83.5 C.

Analysis.Calcd. for C H NO .HC1: C, 57.6%; H, 8.4%; Cl, 10.64%; N; 4.2%. Found: C, 57.41%; H, 8.52%; CI, 10.6%; N, 4.6%.

Example XI.N- (2 (2' methoxyphenoxyisopropyl)- N [2 2' methoxyphenoxfipropyl]amine hydrochloride N [3 (2' methoxyphenoxy)propylJamine (20.8 g.) and 1-(2'-methoxyphenoxy) isopropyl chloride (11.4 g.) are reacted according to method E. The oilobtained by distillation under reduced pressure at 167 C.;180 C./0.1 mm. Hg solidifies. It, is taken up in methanol, ether added, and hydrogen chloride introduced. The salt which precipitates is recrystallizedfrom methanol/ether as lightly pink crystals having a melting point of -132.5 C.134 C.

Analysis.Calcd.: C, 62.91%; H, 7 .39%; Found: C, 63.10%; H, 7.37%; N, 3.94%.

Example XII The acid maleate salts of the products of Examples I, II, III, V, VI and X are prepared by dissolving the free base (0.01 mole) in ether (20 ml.) and adding a solution of maleic acid (0.01 mole) in ether ml.). The salt is recovered by filtration, or-if an oil, by decantation. The oily products "crystallize on chilling. For purification the salts are recrystallized from ethyl acetate.

Example XIII The free base products of Examples I, II, III,'V, VI and X are converted to their hydrochloride salts by passing dry hydrogen chloride into. an other solution of the appropriate free base 0 C. until precipitation is complete; The etheris decanted oil and the -residueriecr'ystallized from ethyl-acetate. r

Example XIV The pamoate salts of the products of Examples I, II, III, V, VI and X are prepared by treating the hydrochloride salts of Example XIII with sodium pamoate (sodium 1,1 methylenebis 2 hydroxy 3 naphthoate in aqueous solution. 'The products are recovered by filtration, washed free of sodium chloride and dried.

Similarly, the'embonate salts are prepared using sodium embonate (sodium 4,4-methylenebis3-hydroxy-2- naphthoate) in place of sodium pamoate.

Example XV The products of Examples I, II, III, V, VI and X are converted to their citrate, acetate, tartrate, di-(p-t'olyoyl) tartrate, ascorbate, sulfate, amsonate and phosphate salts by treatment, in alcohol solution, with an equivalent quantity of the desired acid also in alcohol solution. The products are recovered by filtration.

Example XVI Orth-o methoxyphenoxy ethyl'amine (12.5 parts by weight) was heated to 90 C. and stirred. 9.5 parts by weight of o-arninocarbonyl-phenoxypropylbromide were added within 20 minutes. The mixture was heated for 30 minutes at 90 C. and for a further 20 minutes in the range 20 C. to 120 C. I

The resulting oil was dissolved in chloroform. On the addition of 100 parts by vol. of 2 N-hydrochloric acid a solid was precipitated which was recovered by filtration. The solid was dissolved in ethanol and treated with excess 2 N-sodium hydroxide solution. The white precipitate which formed was filtered oil and recrystallized from ethyl" acetate. This was the free base and had a melting point in the range 128.5 C. to 130 C.

The elementary analysis for N-(o methoxyphenoxy) ethyl-o-aminocarbonyl-phenoxypropylamine v I 19 24 2 4) is C, 66.25; H, 7.02; N, 8.14.

The values found for the product of the process given in this example were as follows: C, 65.92, 66.27; H, 7.12, 7.14; N, 7.78.

This compound when administered intravenously to a cat in a dose level of 0.1 mg. per kg. of body weight caused a marked decrease in blood pressure.

Example XVII The process described in Example XVI may berepeated using 2 mols of o-methoxyphenoxy-N-methylethylamine. Alternatively, the N-methyl derivative can be obtained by forming the secondary amine by combining o-methoxyphenoxy ethylamine and the halo compound and thereafter N-methylating the secondary amine produced, for example, by the use of methyl iodide.

Example XVIII The process described in Example XVI may be repeated using 1 mole of the following compounds in place of o aminocarbonylphenoxypropylbromide.

. m-Cyano-phenoxypentyl bromide 10 N-dimethyl-p-amino carbonyl-phenoxy-butyl chloride p-Cyano-phenoxybutyl bromide p-Isopropylamino carbonyl-phenoxy propylchloride Example XIX o-Methoxyphenoxy ethylamine (22.4 parts by weight) were heated to 110 C. with stirring and 16 parts by weight of p-methoxyphenoxy hexyl chloride were added over a period of 25 minutes and heating was continued for a further minutes.

The mixture was then allowed to cool and was dis solved in 150 parts by volume of chloroform. The organic solution was extracted twice with 75 parts by volume of 2 N hydrochloric acid, washed with parts by volume of 2 N sodium hydroxide and finally washed twice with 50 parts by weight of water.

The remaining organic solution was dried over magnesium sulphate and the organic solvent removed by distillation.

The residue was dissolved in 60 parts by weight of ethanol and the solution poured into a solution of 3.5 parts by weight and maleic acid in ethanol.

The salt formed was recrystallized from ethanol and ethylacetate. It had a melting point in the range 115.5 C. to 118 C. and elementary analysis showed: C, 63.83, 64.06; H, 7.31, 7.27; N, 3.14.

The theoretical analysis for N-(o-methoxyphenoxy ethyD-p-methoxy phenoxyhexylamine maleate is C, 63.78; H, 7.21; N, 2.86.

A single intravenous injection of 0.1 mg. caused a decrease in the blood pressure of a cat for 30 minutes.

Example XX The process of Example XIX was repeated using 17 parts by weight of o-methoxyphenoxy ethylamine and 13 parts by weight of p-methoxyphenoxy butyl bromide.

The latter was added every 15 minutes and heating was continued for 45 minutes at 100 C.

' After drying with magnesium sulphate and removing the solvent the residue was dissolved in ether, dry hydrogen chloride was introduced, the, ether was removed and the residue recrystallized from n-propanol and then methanol/ether. The product which was obtained in 60% yield had a melting point of 121 C. to 122 C.

Elementary analysis gave the following results: C, 62.88, 62.92; H, 7.38, 7.31; N, 3.80, 3.76.

The theoretical values for N-(o-methoxyphen-oxy ethyl)-p-methoxyphenoxy butylamine hydrochloride are C, 62.90; H, 7.34; N, 3.67.

The blood pressure of a cat was decreased for 60 to 90 minutes by a single intravenous injection 0.1 mg./kg. body weight of the above compound.

Example XXI The process of Example XIX was repeated using 24.8 parts by weight of o-methoxyphenoxy ethylamine and 18 parts by weight of o-methoxy phenoxyhexylchloride. The reactants were heated to C. during mixing for 30 minutes and were then heated at 120 C. for a further 90 minutes.

After drying with magnesium sulphate and removing the solvent the residue was dissolved in ethyl acetate, the solution was cooled and the solid precipitation on cooling filtered off.

This was dissolved in methanol and hydrogen chloride introduced into the solution. Ether (100 parts by weight) Was then added and crystals formed which after recovery were found to have a melting point of 121 C. to 122 C.

Elementary analysis gave C, 64.51,. 64.64; H, 7.73,

are c, 64.43; H, 7.87; N, 3.42.

' Theabove compound caused a decrease in blood pressure when administered as a single intravenous injectiongin an amount of 1 mg./kg. body weight for 60 to 90 minutes.

Example XXII The process of Example XIX was repeated using 16.7 parts by weight of o-methoxyphenoxy ethylamine and 17.6 parts by weight of o-methoxyphenoxy pentyl bromide, The addition took place over minutes at. 90 C. and the mixture was heated for a further 30 minutes at 90 C. r e I After drying and. removal of chloroforrn'the free base was crystallized from petrol ether (60 to 80 C.) and then from ethyl acetate and was found to have a melting point of 85.5 C. to 86.5 C.

Elementary analysis gave C, 70.28, 70.39; H, 8.11, 8.22; N, 3.87.

Theoretical .values for N-(o-rnethoxyphenoxy ethyl)-omethoxyphenoxy pentylamine (C H NO are: C, 70.15; H,f8.13; N, 3.90.

The above compound when injected intravenously into a cat in a dose of 0.1 mg./kg. body Weight decreased the blood pressure for 30 to 60 minutes.

The compound also depressed the rate of respiration in mice for 30-60 minutes showing its activity on the central nervous system.

Example XXIII The process of Example XIX was repeated using 39 parts byweight of o-methoxyphenoxy butylamine and o-methoxyphenoxy ethyl chloride. The. addition took place over 40 minutes at a temperature of 140 C. and heating was continued for a further 4 hours.

After drying and removal of chloroform the residue was distilled underreduced pressure and the fraction boiling at 172 C.-l74 C. at 0.7 mm. Hg pressure collected. This was recrystallized from petrol ether/ethyl acetate and gave a crystalline product having a melting point of 54 C. to 55 C.

Elementary analysis gave the following: C, 69.68, 69.69; H,. 7.93, 7.89; N, 3.90.- The theoretical evaluations for N-(o-methoxyphenoxy ethyl)-o-methoxyphenoxy butylamine (C H NO are C, 69.54; H-,'7.88; N, 4.06. I

A single injection of the above compound intravenously at a level of 0.1 mg./kg. body weight decreased the blood pressure of a cat for 30 minutes.

The compound when similarly administered depressed the rate .of respiration in mice showing its activity on .the central nervous system.

Example XXIV 2-(2'emethoxyphenoxy) ethylamine (8.35 parts by weight), 6.73 parts by weight of S-methoxy-chloropent- 2-ene, 42 parts by weight of sodium bicarbonate and 100 parts by volume of absolute ethanol were mixed and boiled under reflux for 18 hours with stirring. The mixture was then cooled, filtered and the filtrate distilled under reduced pressure to remove ethanol. The residue was disilled three times under reduced pressure to give a colourless oil of boiling point' 166 C.177 C. at 0.8 mm.=Hg.

. Elementary analysis gave the values C, 67.85; H, 8.75; N, 5.06.

Theoretical values for N-(S-methoxypent-Z-en-l'-yl)- 2-(2','-methoxypl1enoxy)-ethylamine (C H NO are C, 67.9; H, 8.86; N, 5.29. "A'single intravenous injection of the above com- 12 pound into a cat of 0.1 -mg./kg. body Weight caused a decrease in blood pressure.

The compound obtained above (2 parts by weight) was dissolved in the minimum quantity of'ethanol and added to a solution of maleic acid (0.88 part by weight) in the minimum quantity of ethanol.

The mixture was warmed and ether added until a faint persistent cloudiness appeared. On cooling white crystals .of the. maleate were formed (melting point 89.50 C.- C.). 7.03; N, 3.36.

Example XX V Example XXVI The process of Example XXIv was, repeated using 13.5 parts by weight of 5-n(propoxy)-1-ch1oro pent-2- ene, 14.3 parts by weight of 2-(2'-methoxyphenoxy) ethylamine, 7.2 parts by Weight of sodium bicarbonate and 50 parts by volume of absolute alcohol.

A colourless oil was obtained having a boiling point of C.142 C. at 4 10- mm. Hg.

Elementary analysis of the product gave the following: C, 69.58; H, 9.28; N, 4.19.

The theoretical values for N-/5-(n-propoXy)-pent-2'- ene-4-yl/-2-(2"-methoXyphenOXy) ethylamine are: C, 69.62; H, 9.22; N, 4.78. I

Exdmple XXVII The process ofExample XXIV was repeated using 10.1 parts by weight of 5-methoxy-3-chloropentene-1,

. 12.5 parts by weight 2-(2"-methoxyphenoxy) ethylamine and 6.3 parts by weight of sodium bicarbonate.

The residue was distilled twice very slowly in a short fractionating column and acolourless oil was obtained llriaving a boiling point of 163 C. to 168 C. at 0.5 mm.

A single intravenous injection into a cat of the above compound of 0.1 nag/kg. of body weight caused a decrease in blood pressure.

Example XX VIII The process described in Example XXIV was repeated using 5-ethoxy-3-chloro-pent-1-ene (11.5 parts by weight), 2(2' methoxyphenoxy) ethylamine (12.94 parts by weight) and sodium bicarbonate (6.5 parts by Weight) in 30 parts by volume of ethanol.-

A colourless oil was obtained having a boiling point of 109 C. to 114 C. at 0.03 mm. Hg.

Elementary analysis gave the values: C, 68.48; H, 8.91; N, 4.77.

Theoretical values for N-(S-ethoxy pent-l-en-yl) 2-(2; rsn'ethoxyphenoxy) ethylamine are C, 68.8; H, 8.96; N,

g g Example XXIX The. process described in Example XXIV was repeated using S-n-butoxy 1 chloro pent 1 ene (18 parts by weight), 2(2'-methoxyphen0xy) ethylamine (47 parts by weight) and sodiumbicarbonate (8.6 parts by-weight) in 50 parts by volume of absolute alcohol.

A colourless oil was obtainedhaving: a boiling point of 136 C. to 140 C. at. 9.6)(10 mm. Hg..

Elementary analysis: C, 60.08; H,"

Elementary analysis of this product gave the values: C, 70.52; H, 9.33; N, 4.40.

Theoretical values for 5-(n-butoxy pent 1 en-a-yl) 2-(2'-methoxyphenoxy) ethylamine are C, 70.3; H, 9.44; N, 4.56.

What is claimed is:

1. The compound represented by the formula:

wherein R is methoXy-phenyl and Z is a whole number from O to 1.

7. A compound of claim 6 wherein the CH O group is in the ortho position.

8. N-(Z-hydroxy 3 (2-methoxyphenoxy)propyl)-N- (2- (2'methoxyphenoxy) ethyl) amine.

14 9. The compound represented by the formula:

(CH2) 1H 0-CH CH N-CHg-CHz-CH OR (EH 0 wherein R is methoxy-phenyl and z is a whole number from 0 to 1. I

10. A compound of claim 9 wherein the CH O group is in the ortho position.

11. N (3 4' methoxyphenoxy)propyl) N (2-(2'- methoxyphenoxy)ethyl) amine.

12. The compound represented by the formula:

Reterences Cited by the Examiner UNITED STATES PATENTS 8/41 Alquistet a1. 260-507] 6/52 Kerwin et a1 260507.7

OTHER REFERENCES Denyse: Chemical Abstracts, v01. 41, pages 5971-2 CHARLES B. PARKER, Primary Examiner.

L. ZITVER, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,192,253 June 29, 1965 Ronald J. Boscott et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 69, for "trartrate" read tartrate column 3, line 53, after "base" insert can column 4, line 42, for "CEO-100 ml read (50-100 ml column 5, TABLE I item [5) under the table, before "l04-l05 Cr" insert M.P.

same column 5 TABLE II under the heading "R line 23 thereof, for "0H read OCH "lightly" read slightly column 9, line 27, for "20 C."

--; column 8, line 55, for

read 90 C. line 62, for "o-Amine" read o-Amino column 11, line 67, for "disilled" read distilled column 13, line 16, for "claim wherein" read claim 1 wherein Signed and sealed this 18th day of January 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. THE COMPOUND REPRESENTED BY THE FORMULA
 5. N-(3-ALLYLOXYPROPYL)-N-(2-(2''-METHOXYPHENOXY) ETHYL)AMINE ACID MALEATE. 